Post-translational covalent attachment of ubiquitin and ubiquitin-like proteins has emerged as a predominant cellular regulatory mechanism, with important roles in controlling cell division, signal transduction, embryonic development, endocytic trafficking and the immune response. Indeed, deregulation of the pathways for attaching ubiquitin-like modifications plays a role in a number of diseases, including cancer, birth defects and Parkinson's Disease, and several viruses hijack these pathways during infection. Ubiquitin-like proteins function by remodeling the surface of their target proteins, changing their target' s half-life, enzymatic activity, protein/protein interactions, sub cellular localization or other properties. At least ten different ubiquitin-like modifications exist in mammals, and attachment of different ubiquitin-like proteins to a target leads to different biological consequences. Thus, a key question is how a given ubiquitin-like protein is coordinated with the correct target. Ubiquitin-like proteins are attached via an isopeptide linkage to their targets by the sequential action of El, E2 and in many cases, E3 enzymes. Ubiquitin-like proteins are selected for the pathway by their dedicated El, which coordinates a given ubiquitin-like protein with the right pathway by also selecting the corresponding E2. Despite the wide range of biological processes controlled by ubiquitin-like proteins, the molecular details for how ubiquitin-like proteins are selected by an E1 and coordinated with their E2 remain elusive. Lack of structural data for Els remains a significant limitation in our understanding of ubiquitin-like protein transfer cascades. The proposed research addresses following questions: What are the structures of Els? Which features of the structure are conserved, and which are specific for a particular ubiquitin-like protein family member? How are ubiquitin-like proteins recognized by Els? How are E2s recognized by Els? How do E2s select their particular ubiquitin-like protein? Answering these questions will be of significance to all areas of biology involving regulation by a growing family of ubiquitin-like proteins.